RESEARCH INTERESTS
1. Multicomponent reactions
Multicomponent reactions are processes where three or more molecules react to form a
single product. They are faster and cheaper than classical reactions, since they are done by just
mixing compounds together in one vessel, without isolating any intermediate.
The Yonemitsu condensation1 of indole, an aldehyde and Meldrum’s acid is an example of
multicomponent reaction (Scheme 1). In its original version, only simple achiral aldehydes were
used.
R
O
O
+
H
R
N
H
O
+
O
O
MeCN, 25 °C
O
D,L-proline
O
N
H
R = Alkyl, Aryl
O
+
H2O
O
Yield = 61 - 90 %
Scheme 1
By working with the group of Pr. J. Sapi (University of Reims, France), we extended the
original reaction to some chiral aldehydes such as Garner’s aldehyde (Scheme 2). 2 The
condensation product can be selectively modified into some compounds with potential
biological activities: pyrano- (1) and pyrrolidino-fused (2) tetrahydro--carbolines (helping
memory effect), indolic analogue of azatoxin (3) (anticancer activity). 3 The stereogenic center
of the aldehyde controls the configuration of all the stereocenters generated in the following
steps. Therefore, the final products are obtained in high (> 90%) diastereomeric excess.
N
N
H
+
N
O
boc
O
H
O
boc
O
O
O
MeCN, 25 °C
O
D,L-proline
+
O
O
O
O
N
H
several steps
H
N
O
O
NH
N
H
or
NH
N
H
CO2Me
MeO2C
OH
O
MeOOC
or
N
N
H
O
O
MeO
OMe
OH
(1)
(2)
(3)
Scheme 2
1
Oikawa, Y.; Hirasawa, O.; Yonemitsu, O. Tetrahedron Lett. 1978, 19, 1759-1762.
Dardennes, E.; Kovács-Kulyassa, Á.; Renzetti, A.; Sapi, J.; Laronze, J.-Y. Tetrahedron Lett. 2003, 44, 221-223.
3
(a) Sapi, J.; Laronze, J.-Y. ARKIVOC 2004, vii, 208-222; (b) Dardennes, E.; Kovács-Kulyassa, Á.; Boisbrun, M.;
Petermann, C.; Laronze, J.-Y.; Sapi, J. Tetrahedron: Asymmetry 2005, 16, 1329-1339.
2
We further developed the trimolecular condensation by replacing Meldrum’s acid with other
carbon acids and by varying the heterocycle (Scheme 3).4 In this case, the reaction requires the
presence of TiCl4 and Et3N in stoichiometric amount. Respect to the original version, this
titanium-promoted reaction has the advantage to allow the variation of all of the three reactants
and a greater number of products can be obtained. If the carbon acid is asymmetric, the
condensation product forms in high diastereomeric excess (>90 %).
We are currently trying to make the reaction catalytic and enantioselective. Dr. A.
Macchiarulo (University of Perugia, Italy) is also doing some docking studies in order to find
the more likely biological properties of these compounds.
O
O
Het
+
R1
H
+
R1 O
TiCl4 (1 eq), Et3N (1 eq)
OR2
OR2
Het
CH2Cl2, 0°C-r.t.
R3
R3
Yield = 41 - 90 %
Het = Indoles, Pyrroles and Substituted Furans
R1 = Alkyl, Aryl
R2 = Me, Et, i-Pr
R3 = COOR2, COMe, PO(OEt)2, NO2
Scheme 3
2. Study of reaction mechanisms
We studied the mechanism of the titanium-promoted condensation in collaboration with Dr.
A. Marrone (University of Chieti, Italy) by a combined theoretical and experimental
investigation. Possible reaction pathways have been investigated by DFT calculations, whereas
the reaction intermediates have been identified by NMR and UV-Vis spectrometry. The
trimolecular reaction is probably a sequence of three simpler reactions (Scheme 4): a)
Formation of the enolate ion; b) Knoevenagel condensation between the enolate ion and the
aldehyde; c) Michael addition of the heterocycle to the Knoevenagel adduct. This study was
crucial to understand the role of the metal and to tune the experimental procedure of the
reaction.
We are currently using this model to explain the observed diastereoselectivity.
O
H3CO
1
O
OCH3
TiCl4, Et3N
O
H3CO
IV
Ti
O
2
OCH3
O
IV
Ti
O
i-PrCHO H CO
3
Ti
3
OCH3
Indole
O
IV
O
H3CO
OCH3
H
N
H
Scheme 4
4
Renzetti, A.; Dardennes, E.; Fontana, A.; De Maria, P.; Sapi, J.; Gérard, S. J. Org. Chem. 2008, 73, 6824-6827.